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Nature. 2016 Feb 18;530(7590):349-53. doi: 10.1038/nature16939. Epub 2016 Feb 10.

Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid.

Author information

1
Institute of Neuroimmunology, Institute for Multiple Sclerosis Research, University Medical Centre Göttingen, 37073 Göttingen, Germany.
2
Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany.
3
Department of Structural and Geotechnical Engineering, University of Rome La Sapienza, 00185 Rome, Italy.
4
Department Neurosurgery, University Medical Centre Göttingen, 37075 Göttingen, Germany.
5
Division of Immunology, Department of Pediatrics Dalhousie University, Halifax B3H 4R2, Canada.
6
Departamento de Biología Celular e Inmunología, Centro de Biología Molecular Severo Ochoa, 28049 Madrid, Spain.
7
Medical Clinic and Policlinic IV, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.
8
Department of Neurology, University Hospital, 01307 Dresden, Germany.
9
Max-Planck-Institute for Experimental Medicine, 37075 Göttingen, Germany.

Abstract

In multiple sclerosis, brain-reactive T cells invade the central nervous system (CNS) and induce a self-destructive inflammatory process. T-cell infiltrates are not only found within the parenchyma and the meninges, but also in the cerebrospinal fluid (CSF) that bathes the entire CNS tissue. How the T cells reach the CSF, their functionality, and whether they traffic between the CSF and other CNS compartments remains hypothetical. Here we show that effector T cells enter the CSF from the leptomeninges during Lewis rat experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. While moving through the three-dimensional leptomeningeal network of collagen fibres in a random Brownian walk, T cells were flushed from the surface by the flow of the CSF. The detached cells displayed significantly lower activation levels compared to T cells from the leptomeninges and CNS parenchyma. However, they did not represent a specialized non-pathogenic cellular sub-fraction, as their gene expression profile strongly resembled that of tissue-derived T cells and they fully retained their encephalitogenic potential. T-cell detachment from the leptomeninges was counteracted by integrins VLA-4 and LFA-1 binding to their respective ligands produced by resident macrophages. Chemokine signalling via CCR5/CXCR3 and antigenic stimulation of T cells in contact with the leptomeningeal macrophages enforced their adhesiveness. T cells floating in the CSF were able to reattach to the leptomeninges through steps reminiscent of vascular adhesion in CNS blood vessels, and invade the parenchyma. The molecular/cellular conditions for T-cell reattachment were the same as the requirements for detachment from the leptomeningeal milieu. Our data indicate that the leptomeninges represent a checkpoint at which activated T cells are licensed to enter the CNS parenchyma and non-activated T cells are preferentially released into the CSF, from where they can reach areas of antigen availability and tissue damage.

PMID:
26863192
DOI:
10.1038/nature16939
[Indexed for MEDLINE]

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